Mitochondrial disorders are a diverse group of conditions attributed to dysfunction of the mitochondrial respiratory chain, resulting in a lack of energy production within different tissue types. Disorders can be caused by variants in one of the 37 genes encoded by the mitochondrial genome (mtDNA), or by various nuclear genes which impact mitochondrial function.1 These disorders are clinically heterogeneous and can affect multiple body systems, making them difficult to accurately recognize, diagnose, and trace.
Clinical diagnosis can be a challenge, as patients can have a variety of symptomatology. While some mitochondrial disorders only affect a single organ, many involve multiple organ systems and often present with prominent neurologic and myopathic features. Some of the clinical features fall into a discrete category, such as Kearns-Sayre syndrome (KSS), chronic progressive external ophthalmoplegia (CPEO), mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), myoclonic epilepsy with ragged-red fibers (MERRF), neurogenic weakness with ataxia and retinitis pigmentosa (NARP), or Leigh syndrome (LS). Many of the other clinical phenotypes overlap and may present as seizures, ataxia and spasticity, proximal myopathy, exercise intolerance, general weakness, sensorineural deafness, optic atrophy, or cardiomyopathy. The range in severity and age of onset for many of these disorders can be due to heteroplasmy, the number of affected versus healthy mitochondria in the cells and tissues, and tissue distribution. MNG can detect low levels of heteroplasmy in order to provide clinicians an actionable and medically relevant measurement of affected mtDNA.
As there are multiple types of mtDNA aberrations – SNPs, deletions, and depletion – as well as nuclear variants that cause mitochondrial disorders, MNG offers a range of mtDNA testing which covers this full spectrum. We include mtDNA sequencing and deletion analysis with clinically relevant next-generation sequencing (NGS) panels, giving our clinicians the best chance to diagnose mitochondrial disorders that overlap phenotypes caused by nuclear encoded genes. MNG also features a Comprehensive Cellular Energetics panel, which covers clinically relevant nuclear genes that may cause mitochondrial disorders.
Our Mitochondrial Genome Sequencing is performed by Next-Generation Sequencing (NGS) and can be paired with deletion analysis. Disorders associated with mitochondrial variants can be maternally inherited or sporadic. One of the most commonly characterized single nucleotide variant mtDNA disorders is MELAS, a condition that affects many of the body’s systems, particularly the brain and nervous system (encephalo-) and the muscles (myopathy). MELAS typically appears in childhood after a period of normal development, and the most common clinical presentations are muscle weakness and pain, recurrent headaches, loss of appetite, vomiting, and seizures.2 Similarly, all patients with Leber hereditary optic neuropathy (LHON) carry variants in one of either the MT-ND1, MT-ND4, MT-ND4L, or MT-ND6 genes.3
Mitochondrial deletion syndromes are defined as having a deleted or missing portion of the mtDNA. As with single nucleotide variants in the mtDNA, mitochondrial deletions can also be either maternally inherited or sporadic. Mitochondrial DNA Deletion Analysis at MNG is designed with high sensitivity and specificity to detect deletions in the mitochondrial genome via long range PCR of the entire mtDNA, followed by NGS. KSS is one common deletion disorder, most often affecting the eyes with ophthalmoplegia and retinopathy causing loss of light-sensing tissue in the eye.1 It is genetically characterized by a large-scale deletion resulting in the loss of mitochondrial genes important for mitochondrial protein formation and oxidative phosphorylation.1
Mitochondrial DNA depletion syndromes are a group of autosomal recessive disorders resulting in an overall drop in the numbers of mitochondrial DNA. These disorders can be highly tissue specific, affecting a single organ system or muscle group, or they can be widespread with symptoms ranging from general muscle weakness, stamina, and difficulty feeding, to loss of muscle control and developmental delays with varying age of onset and severity.4 Mitochondrial DNA Depletion Testing is tissue specific and is available for both blood and muscle. Once found, the assessment of causes for mtDNA depletion are an important consideration and include histologic changes (e.g. fibrosis, myofiber necrosis) as well as nuclear gene variants, which are assessed by our Comprehensive mtDNA Depletion Syndromes panel.